Renal cell carcinoma (RCC) is one of the most common malignancies among our Veterans. The main goal of this project is to investigate the role of miRNAs in targeting c-Myc/HIF pathway and thus suppress kidney cancer progression and metastasis using both in vitro and in vivo models. The major barrier or clinical challenge is that despite the recent advances in the understanding of the biological basis of RCC, the management of the disease, especially in the advanced metastatic phase, remains a significant challenge. Molecular understanding of pathways associated with kidney cancer progression may lead to better diagnosis, prognosis and therapeutic strategies against kidney cancer. Based on the preliminary data and published literature, c-Myc/HIF pathway is involved in the progression and metastasis of kidney cancer. We have identified a set of miRNAs that can target c-Myc/HIF pathway and thus may play an important role in inhibition of kidney cancer progression and metastasis through targeting this pathway. The rationale is that the c-Myc/HIF pathway coordinates complex multifunctional events and has a wide range of downstream targets that regulate tumor-associated cell processes such as cell growth, cell cycle, survival, migration, epithelial-mesenchymal transition and angiogenesis in kidney cancer. The role of the miRNA network that regulates the c-Myc/HIF pathway is only beginning to be explored and such studies are lacking in kidney cancer. In this project we will investigate the role of a set of miRNAs in regulation of the c-Myc/HIF pathway that in turn inhibit kidney cancer progression and metastasis. To address this problem, we hypothesize that a set of miRNAs may directly target the c-Myc/HIF pathway and thereby inhibit kidney cancer progression and metastasis. To test this hypothesis, we have proposed a series of in vitro and in vivo experiments described under specific aims. Specific Aim # 1. To investigate the mechanisms of miRNA-mediated inhibition of c-Myc/HIF pathway in suppression of kidney cancer progression and metastasis using both in vitro and in vivo models. Specific Aim # 2: To investigate the molecular mechanisms of alteration of a set of miRNAs in kidney cancer. Specific Aim # 3. To investigate whether expression profile of a set of miRNAs can predict clinical outcome of kidney cancer patients. Accomplishment of this project will be a significant step forward in understanding miRNA-mediated suppression of c-Myc/HIF pathway and designing novel miRNA-based therapeutic strategies for inhibition of progression and metastasis of kidney cancer among our Veterans.